Background <p>Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, but predictive biomarkers of adverse events and outcomes remain limited. Recently, nutritional and inflammatory markers have emerged as potentially predictors of ICI toxicity and efficacy.</p> Materials and methods <p>In this retrospective, monocentric study we evaluated the impact of baseline nutritional and inflammatory markers on ICI safety, activity and efficacy in patients affected by solid tumors treated with mono-immunotherapy. Baseline clinical, nutritional, and inflammatory parameters - including BMI, weight loss, albumin, prognostic nutritional index (PNI), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) - were analyzed in relation to immune-related adverse events (irAEs), best response, progression-free survival (PFS), and overall survival (OS).</p> Results <p>Between 2015 and 2021, 297 patients were included. Median age was 67 (range: 32–91), with 200 (67.3%) patients being male and 218 patients affected by either skin melanoma (41.8%) or lung cancer (31.7%). In 87% of cases, ICI was initiated with palliative intent. Univariate analysis showed associations between high PNI, low NLR, female sex, and first treatment line with increased risk of all-grade irAEs, while no factor predicted grade ≥ 3 toxicity. Higher BMI and receiving immunotherapy as first treatment line were associated with improved response rate and longer OS, while hypoalbuminemia, hyperglicemia, low PNI, and high NLR correlated with worse survival outcomes. In multivariate models, only receiving immunotherapy as first treatment line independently predicted better objective response (HR 0.55) and longer PFS (HR 0.57), while high NLR independently predicted shorter OS (HR 1.93).</p> Conclusion <p>Nutritional and inflammation parameters represent new potential biomarkers which could help reshaping treatment with ICI in cancer patients.</p>